Source Citation

Abstract

Objective

To compare oral and vaginal nystatin with placebo for the treatment of premenopausal
women with presumed candidiasis hypersensitivity syndrome.

Design

Randomized, double-blind, crossover trial.

Setting

University of Alabama at Birmingham School of Medicine. The method and clinical site
of recruitment not specified.

Patients

Patients were premenopausal women, aged 21 to 40 years, with a history of candida
vaginitis that had been aggravated by antibiotics and had responded to nystatin or
other antifungal treatments. Patients had at least 3 of 5 additional features thought
to be common in patients with the candidiasis hypersensitivity syndrome. Of 50 patients
recruited, 42 (84%) completed at least 1 treatment period.

Intervention

During the 32 weeks of the study, each patient followed 4 different treatment regimens,
for 8 weeks each, including each of the 4 possible combinations of oral nystatin (starting
at 500 000 units 4 times daily, doubled after 2 weeks and again after 4 weeks) or
placebo with vaginal nystatin (100 000 units once daily) or placebo.

Main outcome measures

Patients completed general and disorder-specific symptom questionnaires and were examined
every 4 weeks, when fungal cultures were taken.

Main results

The 3 active-treatment regimens and the placebo regimen all reduced vaginal symptoms
(P < 0.001); nystatin regimens were more effective than placebo (P < 0.001). For systemic, nonvaginal symptoms, all 4 treatment regimens reduced
symptoms (P < 0.001), but the active regimens were no more effective than the placebo regimen
(mean difference between all 3 active regimens and placebo was 2%, 95% CI -3% to 7%).
For overall symptoms, the all-nystatin regimen was better than the all-placebo regimen
(P < 0.013), because of the effect on vaginal symptoms and on 4 of 15 nonvaginal
symptoms. There were significant carryover effects of all regimens on the overall
symptom score (P < 0.04). There were no effects of the treatments on physical findings. The treatments
did not affect the rate of positive fungal cultures.

Conclusion

In women with presumed candidiasis hypersensitivity syndrome, nystatin did not alter
systemic symptoms attributed to the syndrome, but did improve vaginal symptoms.

Sources of funding: Critical Illness Research Foundation; National Institutes of Health;
National Institutes of Allergy and Infectious Diseases.

Commentary

This study stems from controversy between the medical community and the lay public
about whether this syndrome is real and treatable, as noted in Bennett's editorial
(1). For the medical community, the syndrome lacks "unambiguous definition," laboratory
tests are unhelpful, and most published reports are in the lay press and are anecdotal,
with no randomized controlled trials to evaluate therapies. The lay press accuses
physicians of failure to listen to patients about how they feel, fear of assessing
atypical therapies, and negligence in studying the illness.

This study by Dismukes and colleagues attempts to objectively evaluate oral or vaginal
antifungal therapy compared with placebo by using presumptive diagnostic criteria.
The methodology is strong; it comprises a priori power calculations, randomization,
blinded evaluation, and crossover strategy. The results indicate a placebo effect
or spontaneous improvement for both vaginal and systemic symptoms, further improvement
in vaginal symptoms with antifungal therapy, but no significant effect of antifungal
therapy compared with placebo on systemic symptoms.

However, there are several possible explanations for a negative study. If diagnostic
criteria are not precise, then all patients may not have had the syndrome. No data
were given about the reliability of the symptom questionnaires or observer variability
in the physical examinations. The significant carryover effect among regimens suggests
an inadequate washout period. The study could not control for diet, which is thought
by some to be an important factor in exacerbations. Of 42 patients, 13 received systemic
antibiotics for up to 14 days, which might affect exacerbations.

The authors should be credited for a well-designed study of rational therapy for this
controversial syndrome, but any of these factors might have biased the study toward
its finding of no difference in systemic symptoms among regimens.